Prostate cancer (PCA) is the most common malignancy and age-related cause of cancer death worldwide. Apart from lung cancer, PCA is the most common form of cancer in men, and the second leading cause of death in American men. In the United States in 2008, an estimated 186,320 new cases of prostate cancer were expected to be diagnosed and about 28,660 men were expected to die of this disease, with African American men and Jamaican men of African decent having the highest incidence rates thereof in the world (American Cancer Society—Cancer Facts and Figures 2008).
Androgens play an important role in the development, growth, and progression of PCA (McConnell, J. D., Urol. Clin. North Am., 1991, 18: 1-13), with the two most important androgens in this regard being testosterone, 90% of which is synthesized in the testes and the remainder (10%) is synthesized by the adrenal glands, and the more potent androgen, dihydrotestosterone (DHT), to which testosterone is converted by the enzyme steroid, 5α-reductase, that is localized primarily in the prostate (Bruchovsky, N. et al., J. Biol. Chem., 1968, 243, 2012-2021).
Huggins et al. introduced androgen deprivation as a therapy for advanced and metastatic PCA in 1941 (Huggins, C. et al., Arch. Surg., 1941, 43, 209-212), and since then, androgen ablation therapy has been shown to produce the most beneficial responses in multiple settings in PCA patients (Denmeade, S. R. et al., Nature Rev. Cancer, 2002, 2: 389-396). Orchiectomy (either surgical, or medical with a GnRH agonist) remains the standard treatment option for most prostate cancer patients, reducing or eliminating androgen production by the testes, but not affecting androgen synthesis in the adrenal glands. Several studies have reported that a combination therapy of orchiectomy with antiandrogens to inhibit the action of adrenal androgens significantly prolongs the survival of PCA patients (Crawford, E. D. et al., New Engl. J. Med., 1989, 321, 419-424; Crawford, E. D. et al., J. Urol., 1992, 147: 417A; and Denis, L., Prostate, 1994, 5 (Suppl.), 17s-22s).
In a recent featured article by Mohler and colleagues (Mohler, J. L. et al., Clin. Cancer Res., 2004, 10, 440-448) it was clearly demonstrated that testosterone and dihydrotestosterone occur in recurrent PCA tissues at levels sufficient to activate androgen receptors. In addition, using microarray-based profiling of isogenic PCA xenograft models, Sawyer and colleagues (Chen, C. D. et al., Nat. Med., 2004, 10, 33-39) found that a modest increase in androgen receptor mRNA was the only change consistently associated with the development of resistance to antiandrogen therapy. Potent and specific compounds that inhibit androgen synthesis in the testes, adrenals, and other tissue may therefore be a more effective for the treatment of PCA (Njar, V. C. O. and Brodie, A. M. H., Current Pharm. Design, 1999, 5: 163-180).
In the testes and adrenal glands, the last step in the biosynthesis of testosterone involves two key reactions that occur sequentially, both reactions being catalyzed by a single enzyme, the cytochrome P450 monooxygenase 17α-hydroxylase/17,20-lyase (CYP17) (Hall, P. F., J. Steroid Biochem. Molec. Biol., 1991, 40, 527-532). Ketoconazole, an antifungal agent that also inhibits P450 enzymes, is also a modest CYP17 inhibitor, and has been used clinically for the treatment of PCA (Trachtenberg, J. et al., J. Urol. 1983, 130, 152-153). It has been reported that careful scheduling of treatment can produce prolonged responses in otherwise castrate-resistant prostate cancer patients (Muscato, J. J. et al., Proc. Am. Assoc. Cancer Res., 1994, 13: 22 (Abstract)). Further, ketoconazole was found to retain activity in advanced PCA patients with progression, despite flutamide withdrawal (Small, E. J. et al., J. Urol., 1997, 157, 1204-1207), and although the drug has now been withdrawn from use because of liver toxicity and other side effects, the ketoconazole results suggest that more potent and selective inhibitors of CYP17 could provide useful agents for treating this disease, even in advanced stages, and in some patients who may appear to be hormone refractory.
A variety of potent steroidal and non-steroidal inhibitors of CYP17 have been reported, some of which having been shown to be potent inhibitors of testosterone production in rodent models (Njar and Brodie, op. cit.). Recently, Jarman and colleagues have described the hormonal impact of their most potent CYP17 inhibitor, abiraterone, in patients with prostate cancer (O'Donnell, A. et al., Br. J. Cancer, 2004, 90: 2317-2325). Some potent CYP17 inhibitors have been shown to also inhibit 5α-reductase and/or be potent antiandrogens with potent antitumor activity in animal models (Njar and Brodie, op. cit., and Long, B. J. et al., Cancer Res., 2000, 60, 6630-6640).
In addition to abiratcronc and to related publications from Barrie and Jarman, Njar et al. disclosed a series of potent CYP17 inhibitors/antiandrogens, the 17-benzazoles, 17-pyrimdinoazoles and 17-diazines in Published International Patent Application WO2006/093993 (University of Maryland). These compounds are potent inhibitors of human CYP17 enzyme, as well as potent antagonists of both wild type and mutant androgen receptors (AR). Particularly-potent CYP17 inhibitors included 3-β-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (Compound 5), 17-(1H-benzimidazole-1-yl)androsta-4,16-diene-3-one (Compound 6), and 3-β-hydroxy-17-(5′-pyrimidyl)androsta-5,16-diene (Compound 15), with IC50 values of 300, 915 and 500 nM, respectively.

Compounds 5, 6, and 15 were effective at competing with the binding of 3H-R1881 (methyltrienolone, a stable synthetic androgen) to both the mutant LNCaP A and the wild-type AR, with a 2.2- to 5-fold higher binding efficiency to the latter. Compounds 5 and 6 were also shown to be potent pure AR antagonists, with cell-growth studies showing that Compounds 5 and 6 inhibit the growth of DHT-stimulated LNCaP and LAPC4 prostate cancer cells with IC50 values in the low micromolar range (i.e., <10 μM). Their inhibitory potencies were comparable to that of casodex, but remarkably superior to that of flutamide.
The pharmacokinetics of compounds 5 and 6 in mice showed that following s.c. administration of 50 mg/kg of compounds 5 and 6, peak plasma levels of 16.82 and 5.15 ng/mL, respectively, occurred after 30 to 60 minutes, both compounds were cleared rapidly from plasma (terminal half-lives of 44.17 and 39.93 minutes, respectively), and neither was detectable at 8 hours. Compound 5 was rapidly converted into a metabolite, tentatively identified as 17-(1H-benzimidazol-1-yl)androsta-3-one.
When tested in vivo, compound 5 proved to be very effective at inhibiting the growth of androgen-dependent LAPC4 human prostate tumor xenograft, while compound 6 proved to be ineffective. Administration of compound 5 (50 mg/kg, twice daily) resulted in a 93.8% reduction (P=0.00065) in the mean final tumor volume compared with controls, and it was also significantly more effective than castration. This was the first example of an anti-hormonal agent (an inhibitor of androgen synthesis (CYP17 inhibitor)/antiandrogen) that is significantly more effective than castration in suppression of androgen-dependent prostate tumor growth. In view of these impressive anti-cancer properties, compound 5 and analogs may be used for the treatment of human prostate cancer, as well as breast cancer, ovarian cancer, and other urogenital cancers or other androgen-related conditions or diseases.
In addition to a compound's efficacy, oral bioavailability is also often an important consideration for the development of molecules as therapeutic agents. The calculated physical properties of Compound 5, for example, satisfies both the Lipinski “rule of five” (Lipinski, C. A., J Pharmacol Toxicol Methods 2000, 44, (1), 235-49) and the recently-proposed rule by Veber et al. (Veber, D. F. et al., J Med Chem 2002, 45, (12), 2615-23) for predicting an improved likelihood of high or drug-like oral bioavailability for new drug candidates, as presented for Compound 5 in Table 1. These data suggest that the compound should be orally bioavailable and, as such, a strong drug candidate.
TABLE 1Molecular Properties of Compound 5 (VN/124-1)Based on Lipinski's and Verber's CriteriaLimitVN/124-1ResultsA. Lipinski CriterionHydrogen bond donors≦51PassHydrogen bond acceptors≦102PassMolecular weight≦500388.2515PassCLogP<55.822FailB. Veber's CriterionNumber of rotatable bonds≦101PassPolar surface area≦140°A238.05°A2PassSum of hydrogen bond donors and≦123Passacceptors
However, some initial studies have indicated that compound 5 has low (˜10%) oral bioavailability in rats. On the basis of the Lipinski's rule, compound 5 has a higher cLogP value (i.e., >5), which could be the major reason for the finding of poor oral bioavailability, as is typical of many steroids. Because oral administrations of drugs are generally preferred, it is important to find ways to improve the oral bioavailability of steroids exemplified by compound 5, as well as the other compounds presented in WO2006/093993.
Additionally, modifications of a compound's structure, such that the serum half-life is extended and Cmax is delayed, are desired, due to better dosing regimens and consistent delivery of the drug to the target in a single dosing.
Further background of the invention is contained in U.S. Pat. No. 5,604,213 (Barrie et al); U.S. Pat. No. 5,994,335 (Brodie et al); U.S. Pat. No. 6,200,965 (Brodie et al); and, U.S. Pat. No. 6,444,683 (Brodie et al).
Certain references cited herein are incorporated by reference in their entirety.